tbuckley/cabot-search huggingface dataset:
Incidence and Progression of Alcohol-Associated Liver Disease After Medical Therapy for Alcohol Use Disorder
Authors: Augustin G. L. Vannier, Jessica E. S. Shay, Vladislav Fomin, Suraj J. Patel, Esperance Schaefer, Russell P. Goodman, Jay Luther
Journal: JAMA Network Open (2022)

Alcohol-associated liver disease (ALD) is one of the most devastating complications of alcohol use disorder (AUD), an increasingly prevalent condition. Medical addiction therapy for AUD may play a role in protecting against the development and progression of ALD.To ascertain whether medical addiction therapy was associated with an altered risk of developing ALD in patients with AUD.This retrospective cohort study used the Mass General Brigham Biobank, an ongoing research initiative that had recruited 127 480 patients between its start in 2010 and August 17, 2021, when data for the present study were retrieved. The mean follow-up duration from AUD diagnosis was 9.2 years. International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnosis codes were used to identify ALD and AUD diagnoses.Medical addiction therapy was defined as the documented use of disulfiram, acamprosate, naltrexone, gabapentin, topiramate, or baclofen. Patients were considered to be treated if they initiated medical addiction therapy before the relevant outcome.Adjusted odds ratios (aORs) for the development of ALD and hepatic decompensation were calculated and adjusted for multiple risk factors.The cohort comprised 9635 patients with AUD, of whom 5821 were male individuals (60.4%), and the mean (SD) age was 54.8 (16.5) years. A total of 1135 patients (11.8%) had ALD and 3906 patients (40.5%) were treated with medical addiction therapy. In multivariable analyses, medical addiction therapy for AUD was associated with decreased incidence of ALD (aOR, 0.37; 95% CI, 0.31-0.43; P < .001). This association was evident for naltrexone (aOR, 0.67; 95% CI, 0.46-0.95; P = .03), gabapentin (aOR, 0.36; 95% CI, 0.30-0.43; P < .001), topiramate (aOR, 0.47; 95% CI, 0.32-0.66; P < .001), and baclofen (aOR, 0.57; 95% CI, 0.36-0.88; P = .01). In addition, pharmacotherapy for AUD was associated with lower incidence of hepatic decompensation in patients with cirrhosis (aOR, 0.35; 95% CI, 0.23-0.53, P < .001), including naltrexone (aOR, 0.27; 95% CI, 0.10-0.64; P = .005) and gabapentin (aOR, 0.36; 95% CI, 0.23-0.56; P < .001). This association persisted even when medical addiction therapy was initiated only after the diagnosis of cirrhosis (aOR, 0.41; 95% CI, 0.23-0.71; P = .002).Results of this study showed that receipt of medical addiction therapy for AUD was associated with reduced incidence and progression of ALD. The associations of individual pharmacotherapy with the outcomes of ALD and hepatic decompensation varied widely.
The gut microbiota prime systemic antiviral immunity via the cGAS-STING-IFN-I axis
Authors: Saskia F. Erttmann, Patrycja Swacha, Kyaw Min Aung, Björn Brindefalk, Hui Jiang, Anetta Härtlova, Bernt Eric Uhlin, Sun N. Wai, Nelson O. Gekara
Journal: Immunity (2022)

The microbiota are vital for immune homeostasis and provide a competitive barrier to bacterial and fungal pathogens. Here, we investigated how gut commensals modulate systemic immunity and response to viral infection. Antibiotic suppression of the gut microbiota reduced systemic tonic type I interferon (IFN-I) and antiviral priming. The microbiota-driven tonic IFN-I-response was dependent on cGAS-STING but not on TLR signaling or direct host-bacteria interactions. Instead, membrane vesicles (MVs) from extracellular bacteria activated the cGAS-STING-IFN-I axis by delivering bacterial DNA into distal host cells. DNA-containing MVs from the gut microbiota were found in circulation and promoted the clearance of both DNA (herpes simplex virus type 1) and RNA (vesicular stomatitis virus) viruses in a cGAS-dependent manner. In summary, this study establishes an important role for the microbiota in peripheral cGAS-STING activation, which promotes host resistance to systemic viral infections. Moreover, it uncovers an underappreciated risk of antibiotic use during viral infections.
Venous or arterial thrombosis and deaths among COVID-19 cases: a European network cohort study
Authors: Edward Burn, Talita Duarte-Salles, Sergio Fernandez-Bertolin, Carlen Reyes, Kristin Kostka, Antonella Delmestri, Peter Rijnbeek, Katia Verhamme, Daniel Prieto-Alhambra
Journal: The Lancet Infectious Diseases (2022)

BackgroundThere are few data on the incidence of thrombosis among COVID-19 cases, with most research concentrated on hospitalised patients. We aimed to estimate the incidence of venous thromboembolism, arterial thromboembolism, and death among COVID-19 cases and to assess the impact of these events on the risks of hospitalisation and death.MethodsWe conducted a distributed network cohort study using primary care records from the Netherlands, Italy, Spain, and the UK, and outpatient specialist records from Germany. The Spanish database was linked to hospital admissions. Participants were followed up from the date of a diagnosis of COVID-19 or positive RT-PCR test for SARS-CoV-2 (index date) for 90 days. The primary study outcomes were venous thromboembolic events, arterial thromboembolic events, and death, all over the 90 days from the index date. We estimated cumulative incidences for the study outcomes. Multistate models were used to calculate adjusted hazard ratios (HRs) for the association between venous thromboembolism or arterial thromboembolism occurrence and risks of hospitalisation or COVID-19 fatality.FindingsOverall, 909 473 COVID-19 cases and 32 329 patients hospitalised with COVID-19 on or after Sept 1, 2020, were studied. The latest index dates across the databases ranged from Jan 30, 2021, to July 31, 2021. Cumulative 90-day incidence of venous thromboembolism ranged from 0·2% to 0·8% among COVID-19 cases, and up to 4·5% for those hospitalised. For arterial thromboembolism, estimates ranged from 0·1% to 0·8% among COVID-19 cases, increasing to 3·1% among those hospitalised. Case fatality ranged from 1·1% to 2·0% among patients with COVID-19, rising to 14·6% for hospitalised patients. The occurrence of venous thromboembolism in patients with COVID-19 was associated with an increased risk of death (adjusted HRs 4·42 [3·07–6·36] for those not hospitalised and 1·63 [1·39–1·90] for those hospitalised), as was the occurrence of arterial thromboembolism (3·16 [2·65–3·75] and 1·93 [1·57–2·37]).InterpretationRisks of venous thromboembolism and arterial thromboembolism were up to 1% among COVID-19 cases, and increased with age, among males, and in those who were hospitalised. Their occurrence was associated with excess mortality, underlying the importance of developing effective treatment strategies that reduce their frequency.FundingEuropean Medicines Agency.
Abstract A010: Integration of clonal composition and tumor heterogeneity reveals novel evolutionary states and intervention targets in ovarian cancer
Authors: Alexandra Lahtinen, Kari Lavikka, Yilin Li, Sanaz Jamalzadeh, Anni Virtanen, Rainer Lehtonen, Olli Carpén, Sakari Hietanen, Kaisa Huhtinen, Antti Häkkinen, Johanna Hynninen, Jaana Oikkonen, Sampsa Hautaniemi
Journal: Cancer Research (2022)

Abstract This abstract is being presented as a short talk in the scientific program. A full abstract is available in the Proffered Abstracts section (PR003) of the Conference Proceedings. Citation Format: Alexandra Lahtinen, Kari Lavikka, Yilin Li, Sanaz Jamalzadeh, Anni Virtanen, Rainer Lehtonen, Olli Carpén, Sakari Hietanen, Kaisa Huhtinen, Antti Häkkinen, Johanna Hynninen, Jaana Oikkonen, Sampsa Hautaniemi. Integration of clonal composition and tumor heterogeneity reveals novel evolutionary states and intervention targets in ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr A010.
Enabling precision monitoring of psoriasis treatment by optoacoustic mesoscopy
Authors: Benedikt Hindelang, Teresa Nau, Ludwig Englert, Andrei Berezhnoi, Felix Lauffer, Ulf Darsow, Tilo Biedermann, Kilian Eyerich, Juan Aguirre, Vasilis Ntziachristos
Journal: Science Translational Medicine (2022)

Psoriasis is a widespread inflammatory skin disease affecting about 2% of the general population. Recently, treatments that specifically target key proinflammatory cytokines driving the disease have been developed to complement conventional therapies with unspecific antiproliferative or anti-inflammatory effects. Efficient monitoring of treatment efficacy in the context of precision medicine and the assessment of new therapeutics require accurate noninvasive readouts of disease progression. However, characterization of psoriasis treatment remains subjective based on visual and palpatory clinical assessment of features observed on the skin surface. We hypothesized that optoacoustic (photoacoustic) mesoscopy could offer label-free assessment of inflammation biomarkers, extracted from three-dimensional (3D) high-resolution images of the human skin, not attainable by other noninvasive methods. We developed a second-generation ultra-broadband optoacoustic mesoscopy system, featuring sub–10-μm resolution and advanced motion correction technology, and performed 80 longitudinal measurements of 20 psoriatic skin plaques in humans under conventional inpatient treatment or receiving biologics with concomitant topical corticosteroid treatment. Optoacoustic image analysis revealed inflammatory and morphological skin features that indicated treatment efficacy with sensitivity, accuracy, and precision that was not possible using clinical metrics. We identify 3D imaging biomarkers that reveal responses to treatment and offer the potential to facilitate disease and treatment characterization. Our findings suggest that optoacoustic mesoscopy may offer a method of choice for yielding both qualitative and quantitative evaluations of skin treatments that are inaccessible by other methods, potentially enabling optimized therapies and precision medicine in dermatology.
Abstract IA014: Insights from comparative oncology
Authors: Carlo Maley
Journal: Cancer Research (2022)

Abstract Comparative biology facilitates the exploration of the major factors that determine cancer susceptibility and resistance. We are only at the beginning of exploring the solutions that nature has found to the problem of preventing cancer, and the weaknesses that have evolved, leaving some animals exceptionally vulnerable to particular types of cancers. Some cancer defenses appear to be cell-intrinsic, such as the propensity of elephant cells to apoptose when they suffer DNA damage. Other defenses appear to depend on the environment, such as the invasion suppressive effects of fibroblasts of some species discovered by Wagner and his colleagues. I will review our early data on patterns of cancer prevalence across species and our initial results supporting Peto’s paradox but showing that contrary to our predictions, life history factors do not seem to explain patterns of cancer prevalence across species. Citation Format: Carlo Maley. Insights from comparative oncology [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr IA014.
ROR1: an orphan becomes apparent
Authors: Thomas J. Kipps
Journal: Blood (2022)

Abstract Since its initial identification in 1992 as a possible class 1 cell-surface receptor without a known parent ligand, receptor tyrosine kinase–like orphan receptor 1 (ROR1) has stimulated research, which has made apparent its significance in embryonic development and cancer. Chronic lymphocytic leukemia (CLL) was the first malignancy found to have distinctive expression of ROR1, which can help distinguish leukemia cells from most noncancer cells. Aside from its potential utility as a diagnostic marker or target for therapy, ROR1 also factors in the pathophysiology of CLL. This review is a report of the studies that have elucidated the expression, biology, and evolving strategies for targeting ROR1 that hold promise for improving the therapy of patients with CLL or other ROR1-expressing malignancies.
Periodontitis pathogen <i>Porphyromonas gingivalis</i> promotes pancreatic tumorigenesis via neutrophil elastase from tumor-associated neutrophils
Authors: Qin Tan, Xiao Ma, Bing Yang, Ye Liu, Yibin Xie, Xijun Wang, Wei Yuan, Jie Ma
Journal: Gut Microbes (2022)

Intratumor microbiome shapes the immune system and influences the outcome of various tumors. Porphyromonas gingivalis (P. gingivalis), the keystone periodontal pathogen, is highly epidemically connected with pancreatic cancer (PC). However, its causative role and the underlining mechanism in promoting PC oncogenesis remain unclear. Here, we illustrated the landscape of intratumor microbiome and its bacterial correlation with oral cavity in PC patients, where P. gingivalis presented both in the oral cavity and tumor tissues. When exposed to P. gingivalis, tumor development was accelerated in orthotopic and subcutaneous PC mouse model, and the cancerous pancreas exhibited a neutrophils-dominated proinflammatory tumor microenvironment. Mechanistically, the intratumoral P. gingivalis promoted PC progression via elevating the secretion of neutrophilic chemokines and neutrophil elastase (NE). Collectively, our study disclosed the bacterial link between periodontitis and PC, and revealed a previously unrecognized mechanism of P. gingivalis in PC pathophysiology, hinting at therapeutic implications.
T‐cell recovery and evidence of persistent immune activation 12 months after severe <scp>COVID</scp>‐19
Authors: Patrick Taeschler, Sarah Adamo, Yun Deng, Carlo Cervia, Yves Zurbuchen, Stéphane Chevrier, Miro E. Raeber, Sara Hasler, Esther Bächli, Alain Rudiger, Melina Stüssi‐Helbling, Lars C. Huber, Bernd Bodenmiller, Onur Boyman, Jakob Nilsson
Journal: Allergy (2022)

T-cell lymphopenia and functional impairment is a hallmark of severe acute coronavirus disease 2019 (COVID-19). How T-cell numbers and function evolve at later timepoints after clinical recovery remains poorly investigated.
A NIR-II emissive polymer AIEgen for imaging-guided photothermal elimination of bacterial infection
Authors: Yue Huang, Dan Li, Deliang Wang, Xiaohui Chen, Lino Ferreira, M. Cristina L. Martins, Youxiang Wang, Qiao Jin, Dong Wang, Ben Zhong Tang, Jian Ji
Journal: Biomaterials (2022)
Ryanodine receptor 2 (RYR2) dysfunction activates the unfolded protein response and perturbs cardiomyocyte maturation
Authors: Yuxuan Guo, Yangpo Cao, Blake D Jardin, Xiaoran Zhang, Pingzhu Zhou, Silvia Guatimosim, Junsen Lin, Zhan Chen, Yueyang Zhang, Neil Mazumdar, Fujian Lu, Qing Ma, Yao-Wei Lu, Mingming Zhao, Da-Zhi Wang, Erdan Dong, William T Pu
Journal: Cardiovascular Research (2022)

Abstract Aims Calcium-handling capacity is a major gauge of cardiomyocyte maturity. Ryanodine receptor 2 (RYR2) is the pre-dominant calcium channel that releases calcium from the sarcoplasmic reticulum/endoplasmic reticulum (SR/ER) to activate cardiomyocyte contraction. Although RYR2 was previously implied as a key regulator of cardiomyocyte maturation, the mechanisms remain unclear. The aim of this study is to solve this problem. Methods and results We performed Cas9/AAV9-mediated somatic mutagenesis to knockout RYR2 specifically in cardiomyocytes in mice. We conducted a genetic mosaic analysis to dissect the cell-autonomous function of RYR2 during cardiomyocyte maturation. We found that RYR2 depletion triggered ultrastructural and transcriptomic defects relevant to cardiomyocyte maturation. These phenotypes were associated with the drastic activation of ER stress pathways. The ER stress alleviator tauroursodeoxycholic acid partially rescued the defects in RYR2-depleted cardiomyocytes. Overexpression of ATF4, a key ER stress transcription factor, recapitulated defects in RYR2-depleted cells. Integrative analysis of RNA-Seq and bioChIP-Seq data revealed that protein biosynthesis-related genes are the major direct downstream targets of ATF4. Conclusion RYR2-regulated ER homeostasis is essential for cardiomyocyte maturation. Severe ER stress perturbs cardiomyocyte maturation primarily through ATF4 activation. The major downstream effector genes of ATF4 are related to protein biosynthesis.
Left Atrial Strain Has Superior Prognostic Value to Ventricular Function and Delayed-Enhancement in Dilated Cardiomyopathy
Authors: Anne G. Raafs, Jacqueline L. Vos, Michiel T.H.M. Henkens, Bram O. Slurink, Job A.J. Verdonschot, Daan Bossers, Kit Roes, Suzanne Gerretsen, Christian Knackstedt, Mark R. Hazebroek, Robin Nijveldt, Stephane R.B. Heymans
Journal: JACC. Cardiovascular imaging (2022)
Potential reduction in healthcare carbon footprint by autonomous artificial intelligence
Authors: Risa M. Wolf, Michael D. Abramoff, Roomasa Channa, Chris Tava, Warren Clarida, Harold P. Lehmann
Journal: npj Digital Medicine (2022)

Healthcare is a large contributor to greenhouse gas (GHG) emissions around the world, given current power generation mix. Telemedicine, with its reduced travel for providers and patients, has been proposed to reduce emissions. Artificial intelligence (AI), and especially autonomous AI, where the medical decision is made without human oversight, has the potential to further reduce healthcare GHG emissions, but concerns have also been expressed about GHG emissions from digital technology, and AI training and inference. In a real-world example, we compared the marginal GHG contribution of an encounter performed by an autonomous AI to that of an in-person specialist encounter. Results show that an 80% reduction may be achievable, and we conclude that autonomous AI has the potential to reduce healthcare GHG emissions.
Developmental research assessing bias would benefit from naturalistic observation data
Authors: Jennifer L. Rennels, Kindy Insouvanh
Journal: Behavioral and Brain Sciences (2022)

Abstract Cesario's critiques and suggestions for redesigning social psychology experiments echo Dahl's (2017) call for developmental researchers to use experimental and naturalistic methods in a complementary manner for understanding children's development. We provide examples of how naturalistic observations can rectify Cesario's missing flaws for developmental studies investigating children's social biases and help researchers derive theories they can then experimentally test.
Improving hard metal implant and soft tissue integration by modulating the “inflammatory-fibrous complex” response
Authors: Peina Huang, Jieyun Xu, Lv Xie, Guangqi Gao, Shoucheng Chen, Zhuohong Gong, Xiaomei Lao, Zhengjie Shan, Jiamin Shi, Zhaocai Zhou, Zhuofan Chen, Yang Cao, Yan Wang, Zetao Chen
Journal: Bioactive Materials (2022)

Soft tissue integration is one major difficulty in the wide applications of metal materials in soft tissue-related areas. The inevitable inflammatory response and subsequent fibrous reaction toward the metal implant is one key response for metal implant-soft tissue integration. It is of great importance to modulate this inflammatory-fibrous response, which is mainly mediated by the multidirectional interaction between fibroblasts and macrophages. In this study, macrophages are induced to generate M1 and M2 macrophage immune microenvironments. Their cytokine profiles have been proven to have potentially multi-regulatory effects on fibroblasts. The multi-reparative effects of soft tissue cells (human gingival fibroblasts) cultured on metal material (titanium alloy disks) in M1 and M2 immune microenvironments are then dissected. Fibroblasts in the M1 immune microenvironment tend to aggravate the inflammatory response in a pro-inflammatory positive feedback loop, while M2 immune microenvironment enhances multiple functions of fibroblasts in soft tissue integration, including soft tissue regeneration, cell adhesion on materials, and contraction to immobilize soft tissue. Enlighted by the close interaction between macrophages and fibroblasts, we propose the concept of an "inflammatory-fibrous complex" to disclose possible methods of precisely and effectively modulating inflammatory and fibrous responses, thus advancing the development of metal soft tissue materials.
Soluble HLA peptidome of pleural effusions is a valuable source for tumor antigens
Authors: Sofia Khazan-Kost, Gal Cafri, Dganit Melamed Kadosh, Navit Mooshayef, Sumit Chatterji, Dan Dominissini, Sigal Manor, Bracha Zisser, Limor Broday, Efrosiniia Talalai, Anat Shemer, Oranit Zadok, Efrat Ofek, Amir Onn, Arie Admon, Michael Peled
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Soluble human leucocyte antigen (sHLA) molecules, released into the plasma, carry their original peptide cargo and provide insight into the protein synthesis and degradation schemes of their source cells and tissues. Other body fluids, such as pleural effusions, may also contain sHLA-peptide complexes, and can potentially serve as a source of tumor antigens since these fluids are drained from the tumor microenvironment. We explored this possibility by developing a methodology for purifying and analyzing large pleural effusion sHLA class I peptidomes of patients with malignancies or benign diseases. Methods Cleared pleural fluids, cell pellets present in the pleural effusions, and the primary tumor cells cultured from cancer patients’ effusions, were used for immunoaffinity purification of the HLA molecules. The recovered HLA peptides were analyzed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) and the resulting LC-MS/MS data were analyzed with the MaxQuant software tool. Selected tumor antigen peptides were tested for their immunogenicity potential with donor peripheral blood mononuclear cells (PBMCs) in an in vitro assay. Results Mass spectrometry analysis of the pleural effusions revealed 39,669 peptides attributable to 11,305 source proteins. The majority of peptides identified from the pleural effusions were defined as HLA ligands that fit the patients’ HLA consensus sequence motifs. The membranal and soluble HLA peptidomes of each individual patient correlated to each other. Additionally, soluble HLA peptidomes from the same patient, obtained at different visits to the clinic, were highly similar. Compared with benign effusions, the soluble HLA peptidomes of malignant pleural effusions were larger and included HLA peptides derived from known tumor-associated antigens, including cancer/testis antigens, lung-related proteins, and vascular endothelial growth factor pathway proteins. Selected tumor-associated antigens that were identified by the immunopeptidomics were able to successfully prime CD8 + T cells. Conclusions Pleural effusions contain sHLA-peptide complexes, and the pleural effusion HLA peptidome of patients with malignant tumors can serve as a rich source of biomarkers for tumor diagnosis and potential candidates for personalized immunotherapy.
The US turns its back on women’s reproductive rights
Authors: Lawrence O Gostin
Journal: BMJ (2022)

Politico published a leaked draft of a US Supreme Court opinion overturning the 1973 landmark case establishing a woman's constitutional right to abortion before fetal viability (Roe v Wade). 1 The leaked opinion concerned a current case, Dobbs v Jackson Women's Health, challenging a Mississippi law that bans abortion after 15 weeks' gestation, except in medical emergencies or the case of severe fetal abnormality. 2 In it, the highly conservative Justice Samuel Alito said, "the Constitution makes no reference to abortion.